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首页> 外文期刊>Cellular Physiology and Biochemistry >Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII
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Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII

机译：内皮素-1和苯肾上腺素诱导的大鼠心室肌细胞cAMP反应元件结合蛋白激活的信号通路：肌醇1、4、5-三磷酸受体和CaMKII的作用

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>Background/Aims: Endothelin-1 (ET-1) and the ?±1-adrenoceptor agonist phenylephrine (PE) activate cAMP response element binding protein (CREB), a transcription factor implicated in cardiac hypertrophy. The signaling pathway involved in CREB activation by these hypertrophic stimuli is poorly understood. We examined signaling pathways for ET-1- or PE-induced cardiac CREB activation. Methods: Western blotting was performed with pharmacological and genetic interventions in rat ventricular myocytes. Results: ET-1 and PE increased CREB phosphorylation, which was inhibited by blockade of phospholipase C, the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, protein kinase C (PKC) or Ca2+-calmodulin-dependent protein kinase II (CaMKII). Intracellular Ca2+ buffering decreased ET-1- and PE-induced CREB phosphorylation by a‰￥80%. Sarcoplasmic reticulum Ca2+ pump inhibitor, inositol 1,4,5-trisphosphate receptor (IP3R) blockers, or type 2 IP3R (IP3R2) knock-out abolished ET-1- or PE-induced CREB phosphorylation. ET-1 and PE increased phosphorylation of CaMKII and ERK1/2, which was eliminated by IP3R blockade/knock-out or PKC inhibition. Activation of CaMKII, but not ERK1/2, by these agonists was sensitive to Ca2+ buffering or to G??6976, the inhibitor of Ca2+-dependent PKC and protein kinase D (PKD). Conclusion: CREB phosphorylation by ET-1 and PE may be mainly mediated by IP3R2/Ca2+-PKC-PKD-CaMKII signaling with a minor contribution by ERK1/2, linked to IP3R2 and Ca2+-independent PKC, in ventricular myocytes.
机译：> 背景/目的： 内皮素-1（ET-1）和α± 1 -肾上腺素受体激动剂去氧肾上腺素（PE）激活cAMP响应元件结合蛋白（CREB），一种与心脏肥大有关的转录因子。这些肥大刺激参与CREB激活的信号传导途径知之甚少。我们检查了ET-1或PE诱导的心脏CREB激活的信号通路。 方法： 用药理学和遗传学手段对大鼠心室肌细胞进行蛋白质印迹分析。 结果： ET-1和PE增加了CREB的磷酸化，这被磷脂酶C（细胞外信号调节激酶1/2（ERK1 / 2）途径）的阻断所抑制，蛋白激酶C（PKC）或Ca 2 + -钙调蛋白依赖性蛋白激酶II（CaMKII）。细胞内Ca 2 + 的缓冲作用使ET-1-和PE诱导的CREB磷酸化降低了80％。肌质网Ca 2 + 泵抑制剂，肌醇1,4,5-三磷酸受体（IP 3 R）阻滞剂或2型IP 3 R（IP 3 R2）敲除消除了ET-1-或PE诱导的CREB磷酸化。 ET-1和PE增加了CaMKII和ERK1 / 2的磷酸化，而IP 3 R阻滞/敲除或PKC抑制作用消除了它们的磷酸化。这些激动剂激活CaMKII，而不激活ERK1 / 2，对Ca 2 + 缓冲液或G ?? 6976（Ca 2 + 依赖性PKC抑制剂）敏感。和蛋白激酶D（PKD）。 结论： ET-1和PE引起的CREB磷酸化可能主要由IP 3 R2 / Ca 2 + 介导。 -PKC-PKD-CaMKII信号由ERK1 / 2贡献较小，与IP 3 R2和Ca 2 + 非依赖性PKC相关，在心室肌细胞中。

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